OA10908A - Mesylate trihydrate salt of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2(1H)-indol-2-one(=ziprasidone) its preparation and its use as dopamine d2 antagonist - Google Patents

Description

Ü9 MESYLATE TRIHYDRATE S ALT OF 5-(2-(4-( 1.2-BENZISOTHIAZOL-3-YL>-J- PIPERAZINYDETH YL>-6-CHLORO-13-DIHYDRO-2( I H>-INDOL-2-ONE (-ZIPRASIDONE),

ÏTS PREPARATION AND TTS USE AS DOPAMINE D2 ANTAGONIST

Backqround of the invention

The invention is directed to the mesylate trihydrate sait of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1 -piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one (hereafter“ziprasidone mesylate trihydrate'), pharmaceutical compositions containing ziprasidonemesylate trihydrate, and methods of administering ziprasidone mesylate trihydrate totreat psychotic diseases. Ziprasidone is a potent psychotic agent and is thereforeuseful for treating various disorders including schizophrenia, migraine pain and anxiety.United States Patent 5,312,925 refers to ziprasidone hydrochloride monohydrate, andStates that ziprasidone hydrochloride monohydrate is substantiaJiy hygroscopicallystable, which alleviates potentiel problems associated with weight changes of the activeingrédient during the manufacture of capsules or tablets. United States Patent5,312,925 is herein incorporated by référencé in rts entirey. Ziprasidone hydrochloridemonohydrate, however, has low aqueous solubility and, as a resuit, is more appropriatefor capsule or tabiet formulation than for injectable dosage forms.

Ziprasidone mesylate trihydrate also possesses hygroscopic stability.Ziprasidone mesylate trihydrate has the added advantage of having significantly greateraqueous solubility than the hydrochloride monohydrate, which makes the mesylatetrihydrate more suitable for injectable dosage forms than the hydrochloridemonohydrate. Further, of the four crystalline forms of ziprasidone mesylate, themesylate trihydrate is the most thermodynamically stable in an aqueous medium atambient conditions. This makes ziprasidone mesylate trihydrate advantageously suitedfor the préparation of consistent and précisé dosage forms involving an aqueousmedium.

Summary of the Invention

The présent invention relates to the mesylate trihydrate sait of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-5-chloro-1,3-dihydro-2H-indol-2-one.

This invention also relates to a pharmaceutical composition for the treatment ofa psychotic disorder, such as schizophrenia, migraine pain or anxiety, comprising anamount of the mesylate trihydrate sait of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl}-S-chloro-1,3-dihydro-2H-indol-2-one that is effective in treating saiddisorder, and a pharmaceutically acceptable carrier. -2-

This invention aiso relates to a method of treating a psychotic disorder, such assehtzophrenia, migraine pain or anxiety, in a mammaJ, including a human, comprisingadministering to said mammai an amount of the mesylate trihydrate sait of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one that iseffective in treating said disorder.

Description of the Drawinqs

Fig. 1 depicts the X-ray powder diffraction spectrum of ziprasidone mesylatetrihydrate expressed as intensity (Cps) versus diffraction angle (two-theta degrees).

Fig. 2 depicts the structure of ziprasidone mesylate trihydrate as determined bysingle crystal X-ray crystaliographic analysis.

Fig. 3 shows a photomicrograph of ziprasidone mesylate trihydrate (prismcrystals).

Table 1 below identifies selected peaks from the spectra of Figure 1 bydiffraction angle (two-theta), d-spacing, maximum intensity (max. int.), and relativeintensity (rel. int.).

Table 1

X-RAY POWDER DIFFRACTION DATA FOR

ZIPRASIDONE MESYLATE TRIHYDRATE

Two-Theta (deqrees) D-spacing (deorees) Max. Int.(counts/sec) Rel. Int.(%) 7.680 11.5025 84.00 8.54 9.657 9.1515 216.00 21.95 10.827 8.1650 48.00 4.88 12.205 7.2455 216.00 21.95 13.203 6.7002 803.00 81.51 13.564 6.5227 329.00 33.43 15.240 5.8089 191.00 19.41 15.507 5.7095 388.00 39.43 15.923 5.5612 836.00 84.96 16.680 5.3106 100.00 10.16 17.000 5.2112 103.00 10.47 17.946 4.9386 428.00 43.50 -0- r r ! ; λ'.

U

Two-Theta fdeqrees^ D-spacing (deorees) Max. Int.(counts/sec) Rel. Int.(%) 18.794 4.7178 383.00 38.92 19.881 4.4622 195.00 19.82 20.491 4.3306 93.00 9.45 21.585 4.1136 603.00 61.28 22.179 4.0047 984.00 100.00 23.472 3.7870 282.00 28.66 24.359 3.6511 240.00 24.39 24.918 3.5705 429.00 43.60 25.280 3.5201 159.00 16.16 26.034 3.4198 221.00 22.46 26.832 3.3199 196.00 19.92 27.594 3.2300 132.00 13.41 28.299 3.1511 261.00 26.52 29.151 3.0608 86.00 8.74 29.819 2.9938 197.00 20.02 30.361 2.9415 138.00 14.02 30.792 2.9014 112.00 11.38 32.448 2.7570 102.00 10.37 33.559 2.6682 73.00 7.42 34.254 2.6149 159.00 16.16 35.069 2.5567 165.00 16.77 35.742 2.5100 84.00 8.54 38.182 2.3551 158.00 16.06 -—-------- -y 25 Detailed Description of the Invention

Ziprasidone mesyiate exists in four distinct crystaiiine forms: ziprasidone mesyiate anhydrous (lath crystal), ziprasidone mesyiate dihydrate (lath crystal),ziprasidone mesyiate dihydrate (needle crystal), and ziprasidone mesyiate trihydrate(prism crystal). Each crystal form has distinct characteristics, such as a distinct powder r· -4- Ü9D8 X-ray diffraction pattern, a distinct single crystal X-ray, and a distinct crystal shape thatcan be observed by photomicrograph. The lath and needle crystals of ziprasidonemesylate dihydrate and the lath crystals of ziprasidone anhydrous are relatively longand thin in contrast to the prism crystals of ziprasidone mesylate trihydrate (Figure 3). 5 Ziprasidone mesylate anhydrous crystals are distinct, though similar in shape to theziprasidone dihydrate lath crystals, The photomicrograph of Figure 3 was obtainedusing an Olympus polarizing microscope (model BH-2) equiped with a halogen iamp,binocular eye piece, polarizing filter and Sony 3ccd video caméra with Sony colorprinter. 10 The characteristic X-ray powder diffraction spectra of ziprasidone mesylate trihydrate is depicted in Figure 1. The structure of ziprasidone mesylate trihydrate asdetermined by single crystal X-ray crystallographic analysis is depicted in Figure 2. TheX-ray powder diffraction spectra of Figure 1 and the single crystal Χ-ray for Figure 2were taken on a Siemens R3RA/V ditfractometer. Ziprasidone mesylate trihydrate is 15 further characterized by its water content which is indicated by its Karl Fischer (KF)value of 9.6 ± 1.0. The ziprasidone mesylate dihydrates (lath and needle) are thesubject of co-pending United States provisional application entitled “Mesylate DihydrateSalts of 5-(2-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one" (Pfizer docket number PC 9573), filed concurrently herewith. The foregoing 20 co-pending United States provisional application is incorporated herein by reference inrts entirety.

In an aqueous medium at ambient température, ziprasidone mesylate trihydrateis the most thermodynamically stable form of the four ziprasidone mesylate forms. Asa resuft, the mesylate trihydrate is the preferred mesylate form for dosage forms 25 involving an aqueous medium. In particular, the mesylate trihydrate is particulariysuited for aqueous dosage forms for parentéral administration. The anhydrousmesylate form was found to be hygroscopic when exposed to air (humidity). Thismakes formulation of dosages diffrcutt because the active ingrédient changes in weightduring the process of preparing the dosages. The relative thermodynamic stability of 30 the three ziprasidone mesylate hydrated crystal forms was determined in a sériés ofbridging experiments where mixtures of the crystal forms were aJlowed to equitibrate.For the bridging experiments, 200 mg samples were aJlowed to equilibrate in water (4mL)at ambient température (22-25 °C). Two samples each of 90/10 (w/w) and 10/90 -5- 01 υ 9 ü 8 (w/w) mixtures of the two different identified polymorphs of ziprasidone mesylate (prismvs. dihydrate (Iath), prism vs. dihydrate (needle), dihydrate (needle) vs. dihydrate (Iath))were evaiuated. After équilibration (12-13 days), the solids were evaluated forpolymorph changes and the supemalants were assayed by HPLC to déterminesolubility. It was found that the stability of the crystal forms to interconversion followsthe trend observed for the solubility of the crystal forms, as shown in Table 2 below.Ziprasidone mesylate trihydrate was thermodynamically favored over the dihydrateforms.

Each of the tour ziprasidone mesylate forms is significantly more soluble thanziprasidone hydrochloride monohydrate which has a solubility of 0.08 mg/ml in waterat ambient température. The solubility of the four ziprasidone mesylate forms isindicated below in Table 2.

Table 2

Aqueous Solubility Of Ziprasidone Mesylate Polymorphs

POLYMORPH SOLUBILITY IN WATER trihydrate 0.73 mg/mL R dihydrate (Iath) 1.11 mg/mL ! dihydrate (needle) 1.10 mg/mL 3 anhydrous 1.27 mg/mL

Ziprasidone mesylate trihydrate may be prepared from the free base(ziprasidone) which is prepared as described in column 4, lines 22-43 of United StatesPatent 5,312,925, referred to above. The free base can also be prepared as describedin United States Patent 5,338,848, the disclosure of which is herein incorporated byréférencé in its entirety. When the intended use is as an injectable formulation, it ispreferred to conduct the préparation under pyrogen-tree and speck-free conditions.Speck-free solvents and reagents can be prepared by filtering them through a 0.45 //mMÎIIipore· nylon filter.

Ziprasidone mesylate trihydrate is prepared by mixing the free base with a mixture of water and organic solvent, preferably tetrahydrofuran, at an organic

sofvent/waîer ratio (v/v) of about 3:7 to about 27:3 at a température ranging from 10°C to 30°C, preferably ambient température (about 22-25°C). Preferably, a THF/water -6- 010908 ratio of 4:7.5 (v/v per unit of free base) is used. The mixture is then heated to atempérature of about 50° C whiie stirring. A dilute solution of methanesulfonic acid isthen prepared (1:4 w/w acid/water) to provide 1.2 équivalents acid, which ts then addedslowly, preferably over a 30 to 60 minute period, to the composition that inciudes thefree base. The reaction mixture is then heated to reflux (about 65 °C) for about 30minutes while protected from light. Afterthe mixture has been heated, it is allowed tocool slowly to ambient température. While the mixture is cooling, ziprasidone mesylatetrihydrate will begin to crystallize out of the mixture. Once the mixture has cooied toambient température, it should be allowed to stir for at least another hour to ensure fullcrystaliization. The trihydrate crystals will appear as large “yeliowish* hexagonalprismatic crystals. The trihydrate crystals can be fittered from the composition througha poly-cloth filter, and then washed consecutiveiy with appropriate volumes of aTHF/water (55/35, v/v) solution and water. When allowed to dry at ambienttempérature, the water content of the crystals has a Karl Fischer value ranging from 8.9-10.1% KF (theoretical KF for the trihydrate is 9.6%). 2prasidone mesylate trihydrate may be administered orally or parenterally,including intravenously or intramuscularly. For parentéral administration, it is preferred,where the use of water is called for, to use stérile water for injection (SWI).Administration through intramuscular injection is preferred. A preferred composition forintramuscular injection is ziprasidone mesylate trihydrate in combination withsulfoxybutyl £-cyclodextnn as carrier, preferably prepared at a ratio of 1:10 (w/w)trihydrate to carrier. Compositions containing ziprasidone mesylate trihydrate incombination with suifoxy ^-cyclodextrin can be prepared as described in co-pendincUnited States provisional applications entitled ‘Method Of Making inclusion Complexes*(Pfizer docket number PC 9563), filed concurrently herewith, and ‘Inclusion ComplexesOf Aryl-Heterocyclic Compounds" (Pfizer docket number PC 8838), filed concurrentlyherewith. Both of the foregoing co-pending United States provisional applications areincorporated herein by référencé in their entirety.

The effective dosage for ziprasidone mesylate trihydrate dépends on theintended route of administration, the indication to be treated, and other factors such asâge and weight of the subject. In the foilowing dosage ranges, the term *mgA* refersmilligrams of the free base (ziprasidone). A recommended range for oral dosina is 5-300 mgA/day, preferably 40-200 mgA/day, more preferably 40-80 mgA/day, in single or -7- 01 0 9 0 8 divided doses. A recommended range for parentéral adiministration, such as injection, is 2.5 mgA/day to 160 mgA/day, and preferably 5-80 mgA/day.

The présent invention is iliustrated by the following examples, but it is not limitedto the details thereof. Uniess otherwise indicated, the préparations described in the 5 following examples were conducted under speck-free and pyrogen-free conditions. Asused in the following examples, THF means tetrahydrofuran and SWI means steriiewater for injection.

Example 1

Purification of 5-r2-(4-(1t2-benzisothiazol-3-vl)-1-piperazinvl1ethvn-e-chloro-10 1,3-d>hydro-2H-indol-2-one

To a ciean and dry glass-lined tank, 46.8 kg of 5-(2-(4-(1,2-benzisothiazol-3-yl)-i -piperazinyl)ethyI]-6-chloro-1,3-dihydro-2H-indol-2-one and 2816.4 L of THF werecharged. The slurry was heated to reflux and held for forty-five minutes to form a hazysolution. The solution was filtered through a 33-inch sparkler precoated with filter aid 15 and backed with a Fulflo® filter (manufactured by Parker Hannifin Corp., Lebanon,Indiana) to a clean, dry glass-lined tank on a lower level. The filtered solution was. concentrated by vacuum distillation, cooled to 5°C, and allowed to stir for two hours.The product was collected by filtration on a centrifuge and washed with cold (0-5 °C)THF. The product was collected and dried under vacuum at 45°C, to yield 40.5 kg of 20 product. The product had a purity of 101.5% (within the typicai range of 100 ± 2% vs.the standard) as determined by an HPLC assay.

Example 2 5-(2-(4-(1-benzisothiazol-3-yl)-1-piperazinyl1ethyl1-6-chioro-1,3- dihydro-2H-indol-2-one methanesulfonate trihydrate 25 A slurry was produced by charging 1000 g of 5-(2-(4-(1,2-benzisothiazol-3-yi)-l -

piperazinyi]ethyl]-e-chloro-1,3-dihydro-2H-indol-2-one, 7500 mL of SWI, and 4000 mLof THF to a 22-liter, three-neck, round-bottom fiask equipped with a heating mantle, anoverhead mechanical stirrer, a condenser, and a température probe. The fiask contentswere protected from light with an aiuminum foil cover. The sluny was heated to 50°C 30 while stirring. Dilute methanesulfonic acid was prepared by combining 188 mL ofmethanesuffonic acid with 812 mL SWI. The dilute methanesulfonic acid was addedslowiy through a dropping tunnel to the reaction mixture. The reaction was heated toreflux (about 65°C), and a dark red solution formed as the reaction mixture was heated. -8- Ü10908

The reaction mixture was allowed to stir under reflux conditions for approximateiy thirtyminutes. After the thirty minute time period, the heating mantle was shut off to aJlowslow cooling of the reaction mixture with stirring. The reaction mixture was allowed tocool with stirring ovemight (about 18 hours). As the reaction mixture cooied, the 5 product crystallized out as large 'yellowish· hexagonal prismatic crystals. The mixturewas aliowed to stir under ambient conditions for one hour. The product was isolatedon a Buchner funnel with a poly cloth filter and was washed consecutively with 1500mL of THF/SWI (65/35, v/v) and 1000 mL of SWI. The crystals were spread over glasstrays and allowed to dry under ambient conditions to a Kar! Fischer value of about 10 9.6%. The product was milled through a Mikro-Samplmill® (manufactured by the

Pulverizing Machinery Division of Mikropul Corp., Summit, New Jersey) equipped witha 0.027 H plate at a speed of 14,000 rpm. The yield was 945 g of product.

The products structure was confirmed as 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl}ethyl]-6-chloro-1,3-dihydro-2H-indo!-2-one methanesulfonate trihydrate by 15 NMR. nC NMR (DMSO-d6): δ 177.1(0), 163.0(0), 153.0(0), 145.0(0), 132.4(0), 129.0(1),127.8(0), 127.7(1), 127.1(0), 126.5(0), 125.6(1), 124.9 91), 122.1(1), 110.6(1), 55.9(2),51.7(2), 47.5(2), 40.7(3), 36.2(2), 27.9(2). Ή NMR (DMSO-d6): δ 10.5 (s, 1 H); 9.8 (br.s, 1H); 8.2 (d, J=8.2 Hz, 1H); 8.1 (d, J=8.2 Hz, 1H); 7.6 (m, 1H), 7.5 (m, 1 H); 7.3 (s,1H), 6.9 (s, 1H); 4.2 (m, 2H); 3.7 (m, 2H); 3.5 (m, 2H), 3.4 (m, 2H); 3.1 (m, 2H); 2.4 (s, 20 3H).

Evaluation of the product by HPLC showed a peak with a rétention timeconesoonding to that of a standard. The HPLC conditions are summanzed in Table3 below.

Table 3

HPLC Conditions: Column: Waters - Puresil C-18 15 cm length x 4.6 mm I.D.(Catalog No. WAT044345) Mobile phase: 0.05 M KH,P0„ pH 3.0:methano! (60:40. v/v) Aow rate: 2.0 mL/minute i Détection: UV, 229 nm Column température: ambient Sample volume: 10j/L

010908

Example 3 5-Γ2-|4-(1,2-benzisothiazol-3-vl)-1-piperazinvllethvl]-6-chloro-1,3-dihydro-2H-indol-2-one methanesulfonate anhvdrous A slurry was produced by charging 350 g of 5-(2-(4-(1,2-benziosothiazol-3~y|)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indoI-2-one and 7000 mL of isopropanol toa 12-literthree-neck, round-bottom flask equipped with a heating mantle, an overheadmechanical stirrer, a condenser, and a température probe. The slurry was heated to50°C while stirring. 65.9 mL of methanesulfonic acid was added slowly through adropping tunnel to the 50°C reaction mixture. A slight exotherm to 55 °C along withthickening of the slurry and lightening of the slurry color were observed. The reactionwas atmospherically distilled to remove 25% of the volume (1750 mL). The slurry wascooled to ambient température and allowed to stir overnight. The product was isolatedon a sintered glass tunnel and washed with fresh isopropanol. The solids were spreadover glass trays and allowed to dry under ambient conditions to a Karl Fischer valueof 0.5%. The yield was 420.3 g of product. Evaluation of the product by HPLC showeda peak with a rétention time corresponding to that of a standard. The purity of theproduct, as determined by HPLC (conditions in Table 3), was 99.8%.

Example 4 5-f2-F4-n-benzisothiazol-3-vl)-1-piperazinynethvn-6-chloro-1,3- dlhydro2H-indol-2-one methanesulfonate dihydrate (needle crystals) A slurry was produced by charging 5 g of 5-(2-(4-(1,2-benzisothiazol-3-yl)-i -piperaziny!Jethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, 37.5 mL of water, and 20 mL ofTHF to a 150 mL, three-neck, round-bottom flask equipped with a heating mantle, anoverhead mechanical stirrer, a condenser, and a température probe. The flask contentswere protected from light with an aluminum foil cover. The slurry was heated to 65 °Cwith stirring. Dilute methanesulfonic acid was prepared by combining 1 mL ofmethanesulfonic acid with 4 mL SWI. The dilute methanesulfonic acid was addedslowly through a dropping funnel to the reaction mixture. The reaction was heated toreflux (about 65°C) and a dark red solution formed. The reaction mixture was aliowedto stir under reflux conditions for approximately thirty minutes. After the thirty minuteperiod, a seed crystal of the needle shaped poiymorph was added to the reactionsolution. Crystal formation started, and the heat was removed to aliow slow cooling ofthe reaction with stining. During cooling at 50°C, a thick 'pinkish' slurry was observed -10- 010908 in the fiask. Water (20 mL) was added to the flask to thin the slurry. The product wasallowed to stir under ambient conditions for one hour. The product was isolated on aBuchner tunnel wfth a paper fitter and the solids were allowed to dry under ambientconditions to a Karl Fischer value of about 6.6%. The yield was 6.03 g of product. The 5 purity of the product, as determined by HPLC (conditions in Table 3), was 99.8%.Example 5 5-f2>i4-(1-ben2isothiazol-3-vl)-1-piperazinvllethvl1-e-chloro-1,3- dihvdro»2H»indol-2-one methanesulfonate dihydrate (lath crystals) A slurry was produced by charging 25 g of 5-[2-[4-(1,2-benzisothiazol-3-yl)-i- 10 piperaziny1]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one and 375 mL of water to a 500 mL,three-neck, round-bottom flask equipped with a heating mantle, an overheadmechanical stirrer, a condenser, and a température probe. The flask contents wereprotected from light with an aluminum foil cover. The slurry was heated to 50-55 °Cwhiie stirring. Methanesulfonic acid (5 mL) was added slowiy through a dropping funnel 15 to the reaction mixture. Thickening of the slurry and lightening of the slurry color wereobserved. The reaction was heated to reflux (about 100°C) and allowed to stir forabout one hour. The heat was removed to allow slow cooling of the reaction withstirring. The reaction solution was allowed to stir under ambient conditions for aboutone hour. The product was isolated on a Buchner funnel with a paper fitter and the 20 solids were allowed to dry under ambient conditions to a Karl Fischer value of about6.2%. The yield was 32.11 g of product. The purity of the product, as determined byHPLC (conditions in Table 3), was 98.7%. » l'S·*'» v *

Claims (7)

1. -11- Û1 0908 CLAIMS We ciaim: 1. 5-(2-(4-(1,2-benzisothiazol-3-yl)-1 -piperazinyl)ethy1)-6-chloro-1,3-dihydro- 2H-indol-2-one mesylate trihydrate. 5
2. 2. A pharmaceutical composition for the treatment of a psychotic disorder comprising an amount of the compound of ciaim 1 that is effective in the treatment ofsaid psychotic disorder and a pharmaceutically acceptable carrier.
3. 3. A method of treating a psychotic disorder in a mammaJ comprisingadministering to said mammal an amount of the compound of ciaim 1 that is effective 10 in the treatment of said psychotic disorder.
4. 4. The method of ciaim 3 wherein said psychotic disorder is schizophrenia,migraine pain or anxiety.
5. 5. The method of ciaim 3 wherein said pyschotic disorder is schizophrenia.
6. 6. The method of ciaim 3 wherein said administration is parentéral15 administration.
7. 7. The method of ciaim 6 wherein said parentéral administration isintramusculaj- injection.